Abstract
BackgroundEarly invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis. The transcription factor FOXO3a is inactivated in various types of solid cancers and the loss of FOXO3a is associated with EMT and tumor metastasis. In this study, we sought to explore whether SPRY2, a regulator of receptor tyrosine kinase (RTK) signaling, is involved in FOXO3a-mediated EMT and metastasis in PDAC.MethodsImmunohistochemistry was performed in 130 paired PDAC tissues and paracarcinomatous pancreatic tissues. Cell proliferation and apoptosis were assessed by cell counting kit and flow cytometry, while cell migration and invasion were evaluated with wound healing and transwell assays. The changes in mRNA and protein levels were estimated by qRT-PCR and western blot. BALB/c nude mice xenograft model was established to evaluate tumorigenesis and metastasis in vivo.ResultsFOXO3a expression was remarkably reduced in PDAC tissues, and correlated with metastasis-associated clinicopathologic characteristics and poor prognosis in patients with PDAC. In addition to the promotion of proliferation and suppression of apoptosis, knockdown of FOXO3a or SPRY2 induced EMT and promoted the migration and invasion of PDAC cells via activation of the β-catenin/TCF4 pathway. Moreover, silencing of SPRY2 reversed the suppressor effects induced by FOXO3a overexpression on EMT-associated migration and invasion of PDAC cells, while blockade of β-catenin reversed the effects of SPRY2 loss. FOXO3a knockdown decreased SPRY2 protein stability, whereas SPRY2 knockdown enhanced β-catenin protein stability. In vivo, FOXO3a knockdown promoted the tumorigenic ability and metastasis of PDAC cells.ConclusionsOur study suggests that knockdown of FOXO3a induces EMT and promotes metastasis of PDAC by activation of the β-catenin/TCF4 pathway through SPRY2. Thus, FOXO3a may represent a candidate therapeutic target in PDAC.
Highlights
Invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis
Expression of FOXO3a in PDAC and paracarcinomatous pancreatic tissues The expression of FOXO3a in 130 paired PDAC tissues and paracarcinomatous pancreatic tissues was detected by IHC staining
FOXO3a protein was found to express at varying levels in PDAC tissues and paracarcinomatous pancreatic tissues (Fig. 1a)
Summary
Invasion and metastasis are responsible for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC), and epithelial-to-mesenchymal transition (EMT) is recognized as a crucial biological progress in driving tumor invasion and metastasis. Metastasis, the process in which tumor cells disseminate from their primary site to distant organ sites of the body, is an early event during progression of PDAC that begins with the epithelial-mesenchymal transition (EMT) [3, 5]. Accumulating evidence implicates that EMT is an initial and prerequisite step for primary tumor cells to become motile and invasive, eventually leading to dissemination and metastasis in multiple solid cancers [9,10,11], including PDAC [3]. Inactivation of FOXO3a can induce EMT and subsequently promote tumor cell invasion and dissemination, indicating that FOXO3a can act as a potential biomarker for the prediction and therapy of tumor metastasis [14]
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